Serotonergic Modulation of Brain Development: Genetic and Pharmacologic Influenc

大脑发育的血清素调节：遗传和药理影响

• 批准号: 7939339
• 负责人: JAY A GINGRICH
• 金额: $ 200万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7939339
• 关键词: Serotonergic; Modulation; Brain; Development; Genetic

DESCRIPTION (provided by applicant): The current application proposes to create a Silvio O. Conte Center for Basic and Translational Mental Health Research to address the role of serotonin (5HT) signaling in brain development. Before 5HT assumes its canonical role as a neurotransmitter, it acts during early stages of neural growth to exert profound effects on brain structure and function. The Center hypothesizes that two modulators of developmental 5HT signaling include: genetic variants and serotonin selective reuptake inhibitors (SSRIs). In the first case, naturally occurring serotonergic polymorphisms are associated with measurable differences in human brain structure and function. In the second case, the fetus receives incidental exposure from maternal use of SSRI medications. Based on animal models and human imaging, the effects of augmented 5HT signaling on brain development may increase vulnerability to mental disorders as a long-term consequence. The Center will investigate both sources of 5HT signaling modulation and hypothesizes that fetal SSRI exposure and 5HTergic genetic variants will produce convergent effects on brain structure, function, and consequently behavior. The Center includes 4 projects and 4 cores that integrate epidemiology, clinical, and animal models to address the central hypothesis. The Center studies ~11,000 children with in utero exposure to SSRIs by following mental and physical health problems through adolescence. A companion project studies newborns exposed to SSRIs in utero using multi-modal neuroimaging and EEG to assess brain structure and function at the earliest ages. The brain effects of early-life SSRI exposure is studied in mouse models using the same multi-modal imaging measures as well as microscopic analyses of cellular properties that may underlie imaging abnormalities. The Center reasons that the influence of genetic modulators of 5HT is likely encoded during early development. We test this hypothesis through genetically stratified newborns and fetal rhesus macaques, and examining genetics, brain imaging, and EEG in a unique, clinically characterized, population at high and low risk for depression. The Center studies of early-life 5HT signaling and brain development should lead to a better understanding of whether some mental disorders have their origins in development-a question highly relevant to the mission of NIMH. PUBLIC HEALTH RELEVANCE: Estimates suggest that >100,000 infants are exposed to SSRIs in utero each year in the U.S. Yet, virtually nothing is known about the effects of SSRIs on fetal brain or their long-term consequences. The role of serotonin in brain development is clearly established in other species and likely applied to humans as well. The proposed Center would address an important public health question about long-term effects of SSRIs on the fetus and provide better understanding of how serotonin can influence brain maturation and behavior.

描述（由申请人提供）：当前申请提议创建 Silvio O. Conte 基础和转化心理健康研究中心，以解决血清素 (5HT) 信号在大脑发育中的作用。在 5HT 发挥其作为神经递质的典型作用之前，它会在神经生长的早期阶段发挥作用，对大脑结构和功能产生深远的影响。该中心假设发育 5HT 信号传导的两种调节剂包括：遗传变异和血清素选择性再摄取抑制剂 (SSRI)。在第一种情况下，自然发生的血清素多态性与人类大脑结构和功能的可测量差异相关。在第二种情况下，胎儿因母亲使用 SSRI 药物而意外接触。根据动物模型和人体成像，增强的 5HT 信号传导对大脑发育的影响可能会增加患精神疾病的长期后果。该中心将研究 5HT 信号调节的两个来源，并假设胎儿 SSRI 暴露和 5HTergic 遗传变异将对大脑结构、功能和行为产生聚合效应。该中心包括 4 个项目和 4 个核心，整合流行病学、临床和动物模型来解决中心假设。该中心对大约 11,000 名在子宫内接触 SSRI 的儿童进行了研究，跟踪整个青春期的心理和身体健康问题。一个配套项目研究了在子宫内接触 SSRI 的新生儿，使用多模式神经影像和脑电图来评估最早年龄的大脑结构和功能。使用相同的多模式成像测量以及对可能导致成像异常的细胞特性进行微观分析，在小鼠模型中研究了生命早期接触 SSRI 的大脑影响。该中心推断，5HT 基因调节剂的影响可能是在早期发育过程中编码的。我们通过对新生儿和胎儿恒河猴进行基因分层，并在具有临床特征的独特的抑郁症高风险和低风险人群中检查遗传学、脑成像和脑电图来检验这一假设。该中心对生命早期 5HT 信号传导和大脑发育的研究应该有助于更好地了解某些精神障碍是否起源于发育——这个问题与 NIMH 的使命高度相关。 公共健康相关性：据估计，美国每年有超过 100,000 名婴儿在子宫内接触 SSRIs。然而，实际上对于 SSRIs 对胎儿大脑的影响或其长期后果一无所知。血清素在大脑发育中的作用在其他物种中已得到明确证实，并且可能也适用于人类。拟议的中心将解决一个重要的公共卫生问题，即 SSRIs 对胎儿的长期影响，并更好地了解血清素如何影响大脑成熟和行为。